The Journal of Experimental Medicine
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Published 25 February 2002. doi:10.1084/jem.20011465
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© Rockefeller University Press, 0022-1007/2002/3/547/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 5, March 4, 2002 547-558

Original Article

Reciprocal Roles for CCAAT/Enhancer Binding Protein (C/EBP) and PU.1 Transcription Factors in Langerhans Cell Commitment

Atsushi Iwama1, Mitsujiro Osawa1, Ryutaro Hirasawa1, Noriko Uchiyama1, Shin Kaneko1, Masafumi Onodera1, Kazuko Shibuya3,6, Akira Shibuya2,6, Charles Vinson4, Daniel G. Tenen5 and Hiromitsu Nakauchi1

1 Department of Immunology, Institute of Basic Medical Sciences, Core Research for Evolutional Science and Technology (CREST) Program of Japan Science and Technology (JST)
2 PRESTO (JST), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
3 Division of Rheumatology, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
4 Laboratory of Biochemistry, National Cancer Institute, Bethesda, MD 20892
5 Harvard Institute of Medicine, Harvard Medical School, Boston, MA 02115
6 RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan

Address correspondence to Atsushi Iwama, Institute of Basic Medical Sciences, Department of Immunology, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Phone: 81-2-9853-7499; Fax: 81-2-9853-6966; E-mail: aiwama{at}md.tsukuba.ac.jp and Hiromitsu Nakauchi, Laboratory of Stem Cell Therapy, Center for Experimental Medicine, The Institute of Medical Sciences, University of Tokyo, 4-6-1 Shirokanedai, Minato-Ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5330; Fax: 81-3-5449-5451; E-mail: nakauchi{at}ims.u-tokyo.ac.jp

Myeloid progenitor cells give rise to a variety of progenies including dendritic cells. However, the mechanism controlling the diversification of myeloid progenitors into each progeny is largely unknown. PU.1 and CCAAT/enhancing binding protein (C/EBP) family transcription factors have been characterized as key regulators for the development and function of the myeloid system. However, the roles of C/EBP transcription factors have not been fully identified because of functional redundancy among family members. Using high titer–retroviral infection, we demonstrate that a dominant-negative C/EBP completely blocked the granulocyte–macrophage commitment of human myeloid progenitors. Alternatively, Langerhans cell (LC) commitment was markedly facilitated in the absence of tumor necrosis factor (TNF){alpha}, a strong inducer of LC development, whereas expression of wild-type C/EBP in myeloid progenitors promoted granulocytic differentiation, and completely inhibited TNF{alpha}-dependent LC development. On the other hand, expression of wild-type PU.1 in myeloid progenitors triggered LC development in the absence of TNF{alpha}, and its instructive effect was canceled by coexpressed C/EBP. Our findings establish reciprocal roles for C/EBP and PU.1 in LC development, and provide new insight into the molecular mechanism of LC development, which has not yet been well characterized.

Key Words: myeloid differentiation • lineage commitment • dendritic cells • eosinophils • dominant-negative C/EBP


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